DESCRIPTION: Deposition of amyloid-B peptide (AB) in the CNS occurs during normal aging and is accelerated by Alzheimer's Disease. AB is implicated in the neuropathology of AD and related disorders. Apolipoproteins J and E (apoJ, apoE) co-localize with the senile plaques and congophilic angiopathy of AD. ApoJ is the major protein carrier of AB in body fluids and across biological membranes. ApoE4 is a risk factor for AD, and the amount of AB deposition in AD brains is dependent on the number of copies of the e4 allele. Recent studies suggest a major role of the blood-brain barrier (BBB) in determining the concentrations of AB in the CNS. The BBB has a dual role: 1) to control the entry of plasma derived AB and the proteins to which it binds into the CNS, and 2) to regulate the levels of brain-derived AB via clearance mechanisms. AB putative receptors (e.g., RAGE) and lipoprotein receptors (e.g., gp330/megalin, LRP-1) in cerebral endothelial cells and in brain mediate the BBB and CNS transport of free AB and/or AB complexed to apoJ and apoE. Our hypothesis is that apoJ and apoE differentially regulate the BBB and CNS transport of brain-derived and plasma-derived Aft, and that aging predisposes to CNS AJ3 accumulation, formation of amyloid lesions and AB-related cytotoxic effects by upsetting the balance in apolipoprotein-mediated BBB and CNS transport of Aft, and this is further enhanced by AD, in transgenic (Tg) models of brain amvloidosis - Alzheimer's type and by the E4/E4 genotype. We will study the BBB and CNS transport of AB/apolipoproteins during normal aging (aim 1), in Tg mice expressing human AL precursor protein (APP) (aim 2) and in TgAPP mice expressing human apoE2, E3 and E4 on a mouse null apoE background (aim 3). Since apoJ, apoE and AB receptors/transporters are potential drug targets, understanding their function in vivo in different animal models should help developing strategies to prevent and/or decelerate brain accumulation of AB, amyloid formation and associated cytotoxic effects.